Dry eye, also known generically as keratoconjunctivitis sicca, is a common opthalmological disorder affecting millions of Americans each year. Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.
Dry eye may afflict an individual with varying severity. Dry eye is particularly widespread among post-menopausal women due to hormonal changes following the cessation of fertility. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eye lid and the eye surface. In severe cases, vision may be substantially impaired. Other diseases, such as Sjogren's disease and cicatricial pemphigoid manifest dry eye complications.
The etiopathogenic classification of dry eye was first developed in 1995 by the National Eye Institute/Industry Dry Eye Workshop and was further updated in the January 2007 definition. The Ocular Surface, vol. 5, no. 2, 75-92 (2007). The major classes of dry eye include aqueous tear-deficient dry eye and evaporative dry eye. Aqueous tear-deficient dry eye comprises two major subclasses, Sjogren syndrome dry eye and non-Sjogren syndrome dry eye (primary and secondary lacrimal gland deficiencies, obstruction of the lacrimal gland ducts, reflex hyposecretion, reflex motor block). Evaporative dry eye, resulting from excessive water loss from the exposed ocular surface in the presence of normal lacrimal secretory function, comprises the subclasses of intrinsic causes (meibomian gland dysfunction, lid aperture and lid/globe disorders, low blink rate) and extrinsic causes (ocular surface disorders and disease, contact lens wear, allergic conjunctivitis such as vernal keratoconjunctivitis).
Although it appears that dry eye may result from a number of unrelated pathogenic causes, all presentations of the complication share a common effect, that is the breakdown of the pre-ocular tear film, which results in dehydration of the exposed outer surface and many of the symptoms outlined above (Lemp, Report of the national Eye Institute/Industry workshop on Clinical Trials in Dry Eyes, the CLAO Journal, vol. 21, no. 4, pp 221-231 (1995).
Practitioners have taken several approaches to the treatment of dry eye. One common approach has been to supplement and stabilize the ocular tear film using so-called artificial tears instilled throughout the day. Other approaches include the use of ocular inserts that provide a tear substitute or stimulation of endogenous tear production.
Examples of the tear substitution approach include the use of buffered, isotonic saline solutions, aqueous solutions containing water soluble polymers that render the solutions more viscous and thus less easily shed by the eye. Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids and oils. Phospholipid compositions have been shown to be useful in treating dry eye; see, e.g. McCulley and Shine, Tear film structure and dry eye, Contactologio, vol. 20(4), pp 145-9 (1998). Phosphilipid drug delivery systems involving phospholipids, propellants and an active substance are also known, see U.S. Pat. No. 5,174,988.
Another approach involves the provision of lubricating substances in lieu of artificial tears. For example, U.S. Pat. No. 4,818,537 (Guo) discloses the use of a lubricating liposome-based composition, and U.S. Pat. No. 5,800,807 (Hu et al.) discloses compositions containing glycerin and propylene glycol for treating dry eye.
Although these approaches have met with some success, problems in the treatment of dry eye nevertheless remain. The use of tear substitutes, while temporarily effective, generally requires repeated application over the course of a patient's waking hours. It is not uncommon for a patient to have to apply artificial tear solution ten to twenty times over the course of the day. Such an undertaking is not only cumbersome and time consuming, but is also potentially very expensive. Transient symptoms of dry eye associated with refractive surgery have been reported to last in some cases from six weeks to six months or more following surgery.
Aside from efforts directed primarily to the alleviation of symptoms associated with dry eye, methods and compositions directed to treatment of the dry eye condition have also been pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) discloses the use of sex steroids such as conjugated estrogens to treat dry eye conditions in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen) discloses the use of finely divided calcium ion compositions to stimulate pre-ocular tear film production; and U.S. Pat. No. 4,966,773 (Gressel et al.) discloses the use of microfine particles of one or more retinoids for ocular tissue normalization.
Some literature reports suggest that patients suffering from dry eye syndrome disproportionately exhibit the hallmarks of excessive inflammation in relevant ocular tissues, such as the lacrimal and meibomian glands. The use of various compounds to treat dry eye patients, such as steroids e.g. U.S. Pat. No. 5,968,912; Marsh, et al., Topical nonpreserved methylprednisolone therapty for keratoconjunctivitis sicca in Sjogren syndrome, Opthalmology, 106(5): 881-816 (1999); Plugfelder et al, U.S. Pat. No. 6,153,607]; cytokine release inhibitors (Yanni, J. M.; et al WO0003705 A1), cyclosporine A [Tauber, J. Adv. Exp. Med. Biol. 1998, 438, (Lacrimal Gland, Tear From and Dry Eye Syndromes 2), 969] and 15-HETE (Yanni et al., U.S. Pat. No. 5,696,166) has been disclosed.
In addition to dry eye, Jak3 inhibitors may be useful in the treatment of other inflammation-linked ocular disorders, including but not limited to glaucoma, uveitis, diabetic retinopathy and age-related macular degeneration. A CNIB-funded study found that patients having the inflammatory biomarker, anticardiolipin, were four times more likely to progress in glaucoma. Jak3 inhibitors have previously been suggested for the treatment of diabetes, although there appears no suggestion for diabetic retinopathy in particular. Cetkovic-Cvrle, M. and Uckun, F. M., Arch Immunol Ther Exp (Warsz), 52(2), 69-82 (2004). Rodrigues found that the isolation of immunoglobulins, complement proteins, cytokines and activated microglia, in retinal pigment epithelium (RPE) cells and drusen provided evidence for the role of inflammation in dry age-related macular degeneration. Rodrigues E. B., Opthalmologica, 221(3)143-52 (2007).